Certain 4-phenoxy-3-heteroarylmethyl or ethyl sulfamyl benzoic acid derivatives

ABSTRACT

Compounds of the general formula ##SPC1## 
     In which R 1  represents a straight or branched C 1  -C 6  alkyl, alkenyl or alkynyl radical, or a C 1  -C 3  alkyl radical substituted with phenyl, halophenyl, trifluoromethylphenyl, (lower alkoxy)phenyl, or with a 5-membered or 6-membered heterocyclic ring containing not more than two heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen; R 2  stands for a phenyl radical, optionally being substituted with halogen, lower alkyl, hydroxy, or lower alkoxy; X and Y stand for oxygen or sulphur; their salts and esters and methods for their preparation. The compounds of the invention possess an outstanding diuretic and saluretic activity with a very low excretion of potassium ions and a low toxicity.

This application is a division of application Ser. No. 370,609, filedJune 18, 1973, now U.S. Pat. No. 3,950,376 for NEW SULFAMYLBENZOIC ACIDDERIVATIVES.

This invention relates to a series of new compounds, their salts andesters and to methods for the preparation of the compounds having theformula: ##SPC2##

In which R₁ represents a straight or branched C₁ --C₆ alkyl, alkenyl oralkynyl radical, or a C₁ --C₃ alkyl radical substituted with phenyl,halophenyl, trifluoromethylphenyl, (lower alkoxy)phenyl, or with a5-membered or 6-membered heterocyclic ring containing not more than twoheteroatoms selected from the group consisting of oxygen, sulphur andnitrogen; R₂ stands for a phenyl radical, optionally being substitutedwith halogen, lower alkyl, hydroxy, or lower akoxy; X and Y stand foroxygen or sulphur.

In particular, R₁ may represent e.g. a methyl, ethyl, propyl, isopropyl,butyl, isobutyl or tert. butyl radical, or one of the different isomericpentyl, or hexyl radicals, an alkenyl or alkynyl radical, e.g. an allyl,or propargyl radical, a benzyl or phenethyl radical, a 2-, 3-, or4-pyridylmethyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl,thiazolylmethyl, or imidazolylmethyl radical; or one of thecorresponding ethyl radicals.

Of particular value are the compounds of the invention in which R₁ isselected from the group consisting of straight or branched C₃ -C₅ alkylradicals, and a methyl radical being substituted with phenyl, furyl,thienyl, and pyridyl, and the correspondingly substituted ethylradicals.

The substituents R₁ and R₂ of formula I can be further substituted indifferent positions with different groups, such as one or more halogenatoms, e.g. chlorine or bromine atoms, lower alkyl, halo-lower alkyl,e.g. trifluoromethyl; hydroxy groups, which may be etherified, e.g.lower alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxyor isobutoxy, or esterified with lower aliphatic carboxylic acids, suchas lower alkanoic acids, e.g. acetic, propionic or pivalic acid, loweralkenoic acids, e.g. acrylic or methacrylic acid, or with loweraliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric,adipic, malcic or fumaric acid or their acid esters with lower alkanols,e.g. methanol or ethanol; or etherified mercapto groups such asmethylthio, ethylthio, isopropylthio, butylthio or isobutylthioradicals.

Whenever the expression "lower alkyl" is used in the foregoing and inthe following it stands for a straight or branched alkyl radical withfrom 1 to 6 carbon atoms in the chain.

The salts of the compounds of the invention are pharmaceuticallyacceptable salts, and include, for example, alkali metal salts, alkalineearth metal salts, the ammonium salt or amine salts formed, forinstance, from mono-, di- or trialkanolamines or cyclic amines. Theesters of the compounds are preferably derived from lower aliphaticalcohols, cyanomethanol and benzyl alcohol.

It has surprisingly been found that the compounds of the inventionpossess an outstanding diuretic and saluretic activity with a very lowexcretion of potassium ions and a low toxicity which make the presentcompounds particularly valuable in human or veterinary practice.

In the present series of compounds, the position of the YR₁ group isessential, as according to experiments performed in connection with thepresent invention, it has been found that the compounds of the followingformula ##SPC3##

in which R₁, R₂, X and Y have the above meaning, and in which the YR₁group is placed in the 2-position have a negligible diuretic effect.

The compounds of the invention are more stable than the known benzoicacid derivatives containing an amino or substituted amino group, e.g.furosemide, which are light-sensitive and must be stored in darkreceptacles.

Further the compounds of the invention are also extremely valuable inthe treatment of patients suffering from hypersensitivity towardssulfanilamide diuretics and metanilamide diuretics because there existsno cross hypersensitivity between these compounds and the compounds ofthe invention.

The present compounds are effective after oral, enteral or parenteraladministration, and are preferably prescribed in the form of tablets,pills, dragees, or capsules containing the free acid or salts thereofwith atoxic bases, or the esters thereof, mixed with carriers and/orauxiliary agents.

Salts, which are soluble in water, may with advantage be administered byinjection. The parenteral preparations are in particular useful in thetreatment of conditions in which a quick dehydration is desirable, e.g.in the intensive therapy in the case of oedemas in the lung. In thecontinuous therapy of patients suffering from e.g. hypertension, thetablets or capsules may be the appropriate form of pharmaceuticalpreparation owing to the prolonged effect obtained when the drug isgiven orally, in particular in the form of sustained-release tablets.

In the treatment of heart failure and hypertension such tablets mayadvantageously contain other active components, as specified below.

Another object of the invention resides in the selection of a dose ofone of the compounds of the invention or their salts or esters which canbe administered so that the desired activity is achieved withoutsimultaneous secondary effects. In such a dosage unit the compounds areconveniently administered as a pharmaceutical preparation containingfrom 0.1 mg to 25 mg of the active compound. The compounds of formula Iare preferably administered in amounts from 0.25 mg to 10 mg. By theterm "dosage unit" is meant a unitary, i.e. a single dose capable ofbeing administered to a patient, and which may be readily handled andpacked, remaining as a physically stable unit dose, comprising eitherthe active material as such or in a mixture of it with a pharmaceuticalcarrier and auxiliary agents.

In the form of a dosage unit the compounds may be administered one ormore times a day at appropriate intervals. The daily dose usuallyamounts to from 0.5 to 50 mg always depending, however, on the conditionof the patients and according to the prescription of the medicalpractitioner.

In pharmaceutical compositions containing the compounds of theinvention, organic or inorganic, solid or liquid carriers suitable fororal, enteral, or parenteral administration can be used to make up thecomposition. Gelatine, lactose, starch, magnesium stearate, talc,vegetable and animal fats and oils, gum, polyalkylene glycol, or otherknown carriers for medicaments are all suitable as carriers.

In the pharmaceutical compositions, the proportion of therapeuticallyactive material to carrier substances can vary between 0.2 percent and90 percent.

The compositions may further contain other therapeutic compounds,applied in the treatment of, for example oedemas and hypertension,besides the well-known auxiliary agents. Such other compounds may be,for instance, Veratrum- or Rauwolfia alkaloids, e.g. reserpine,rescinnamine or protoveratrine or synthetic hypotensive compounds, e.g.hydralazine, or other diuretics and saluretics, such as the well-knownbenzolthiadiazines, e.g. hydroflumethiazide, bendroflumethiazide, andthe like. Potassium-sparing diuretics, e.g. triamterene, may also beused in the preparation of the compositions. For some purposes it may bedesirable to add small amounts of aldosterone antagonists, e.g.spironolactone.

It is another object of the invention to provide methods of preparingthe compounds of the invention.

The compounds of the invention may be prepared by various methods, forexample according to the following reaction scheme: ##SPC4##

in which formulae the substituents R₁, R₂, X, and Y are as definedbefore, and Hal stands for a halogen atom, preferably chlorine orfluorine.

The reaction between a compound of the formula II and a compound R₂ XH,in which X and R₂ have the above meaning, is effected by heating thecomponents in the presence of an acid binding agent, in a suitablesolvent or, when appropriate by using the compound R₂ XH as solvent. Thetemperature depends upon the reaction components used and will in mostcases preferably be about the boiling poing of the solvent.

If desired, an ester of a compound of the formula II can be used in thereactions, whereby the compound of the formula I is obtained as anester. The corresponding free acid may, optionally, be obtained by asubsequent saponification. In case of the desired product being an esterand the starting material of formula II being the free acid, anesterification can be performed either before or after the alkylationprocess.

The starting materials of the formula II are new and interestingcompounds which also possess valuable diuretic and saluretic activities.

The compounds of formula II (Y=S) may be prepared from a3-amino-4-halo-5-sulphamylbenzoic acid, which compounds are known or canbe produced analogous with the known ones, by diazotation and subsequenttreatment with sodium sulfide, whereby a5,5'-dicarboxy-2,2'-dihalo-3,3'disulphamyl-diphenyl disulfide isproduced. This compound is then reduced to3-mercapto-4-halo-5-sulphamylbenzoic acid, for instance by using zinc inglacial acetic acid. The resulting mercapto compound thereafter isalkylated to the desired staring material of the formula II (Y=S).

As generally known for the transformation of aromatic amines to thecorresponding hydroxy compounds, the starting materials of formula II inwhich Y stands for oxygen can be produced from the above3-amino-4-halo-5-sulphamylbenzoic acids by diazotation and subsequentreplacement of the diazonium group in the 3-position by a hydroxy group.

The compound thus obtained can under conditions analogous to thosedescribed above for the corresponding mercapto derivatives be alkylatedto the starting materials of formula II (Y=O).

Appropriately the alkylation can be performed either on the free acid offormula II or on one of its esters by treatment with a compound R₁ Z inwhich R₁ has the above meaning, and Z stands for a halogen atom, e.g. abromine atom, or an alkyl- or arylsulphonyloxy group, or with a di-R₁-sulphate, a diazo derivative of the formula R₁ N₂ or a quaternaryderivative of the formula R₁ N⁺(Alk)₃, in which R₁ has the above meaningand Alk stands for alkyl with from 1 to 6 carbon atoms.

The compounds of the invention in which Y stands for S may also beprepared according to the following reaction scheme: ##SPC5##

in which formulae the substituents R₁, R₂, X, and Y are as definedbefore; and Hal stands for a halogen atom, preferably chlorine. Thereaction is performed by treating the compound of formula III withammonia, either with liquid ammonia or preferably concentrated aqueousammonia, or under reaction conditions where ammonia is liberated, suchas treatment with ammonium carbonate or hexamethylene tetramine, ifnecessary by heating. The isolation of the compounds of formula I can beperformed by means of well-known standard procedures.

When esters of the compounds of the formula III are used in thereaction, the compounds of the formula I are obtained as esters, or insome cases due to an aminolysis as amides. The corresponding free acidsmay, optionally, be obtained by a subsequent saponification. In case ofthe desired product being an ester and the starting material of formulaIII being the free acid, an esterification can be performed eitherbefore or after the amidation process.

The starting compounds of formula III can be prepared as follows:

The well-known 4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid is reduced,for instance by means of sodium sulphite in known manner to thecorresponding sulfinic acid which is obtained as e.g. the mono sodiumsalt of 4-chloro-5-nitro-3-sulfinobenzoic acid. This compound is treatedwith a compound of the formula R₂ XH, in which R₂ and X are as definedbefore, preferably by heating the components, if necessary in thepresence of an acid binding agent, in a suitable solvent, or whenappropriate, by using the compound R₂ XH as solvent. The reaction can beperformed at room temperature or at elevated temperature up to about theboiling point of the solvent used. By this reaction the R₂ X radicalreplaces the 4-chloro atom whereafter the reaction product is isolatede.g. as the mono sodium salt of a 5-nitro-4-R₂ X-3-sulfinobenzoic acid.The sulfinic acid group and the nitro group of these compounds arereduced throughout, e.g. with zinc and acids, such as hydrochloric acid,to the corresponding 5-amino-4-R₂ X-3-mercaptobenzoic acid.

In order to obtain the corresponding 3-hydroxy-compound, a 3-amino-4-R₂X-5-nitrobenzoic acid, which is a known compound or can be producedanalogous with the known compounds, is diazotized and the resultingdiazonium group replaced by hydroxyl as generally known for thetransformation of aromatic amines to hydroxy compounds, yielding a3-hydroxy-4-R₂ X-5-nitrobenzoic acid, in which the 5-nitro groups isthereafter reduced, yielding the corresponding 5-amino-3-hydroxy-4-R₂X-benzoic acid.

The 5-amino-4-R₂ X-3-YH-benzoic acids (Y = oxygen or sulphur) thusobtained are then alkylated, whereby the corresponding 3-YR₁-derivatives are obtained. This alkylation can be performed either onthe free acid or on one of its salts or esters as described above inconnection with the preparation of the starting materials of formula II.

The 5-amino-4-R₂ X-3-YR₁ -benzoic acids thus obtained are thereafterthrough their corresponding diazonium salts and by means of thewell-known Mee wein-reaction transferred into the corresponding5-halosulfonyl derivatives of the general formula III.

The compounds of the invention can further be prepared by an alkylationaccording to the following reaction scheme: ##SPC6##

in which formulae the substituents R₁, R₂, and X are as defined before.This alkylation can be performed either on the free acid or on one ofits salts or esters as described above in connection with thepreparation of the starting materials of formula II. The isolation ofthe compounds of formula I can be performed by means of well-knownstandard procedures.

When esters of the compounds of the formula IV are used in the reaction,the compounds of the formula I are obtained as esters. The correspondingfree acids may, optionally, be obtained by a subsequent saponification.In case of the desired product being an ester and the starting materialof formula IV being the free acid, an esterification can be performed.

The starting compounds, 5-sulfamyl-4-R₂ X-3-mercaptobenzoic acids, offormula IV can be prepared from 5-amino-4-R₂ X-3-mercaptobenzoic acids,which are prepared as described above in connection with the preparationof the starting materials of formula III. These compounds are oxydizedto their corresponding disulfides, i.e.5,5'-diamino-3,3'-dicarboxy-6,6'-di-R₂ X-diphenyl disulfides. Thesedisulfides are thereafter through their corresponding diazonium saltsand by means of the well-known Meerwein-reaction, transferred into thecorresponding 5,5'-dihalosulfonyl disulfides. By treating theseintermediates with ammonia, the corresponding 5,5'-disulfamyl disulfidesare obtained. These 5,5'-disulfamyl-3,3'-dicarboxy-6,6'-di-R₂ X-diphenyldisulfides are by treatment with dithionite or other suitable reducingagents transferred into the starting compounds of formula IV. Ifdesired, esters of these compounds can be prepared by a simpleesterification process before the compounds are subjected to thealkylation process according to the invention.

The reactions described above for the production of the startingmaterials of formula II, III, and IV are all well-known to the skilledchemist, and the reaction products are easily isolated.

The invention will now be illustrated by the following non-limitingExamples from which the details of the embodiments will be apparent.

EXAMPLE 1 4-Chloro-3-mercapto-5-sulfamylbenzoic acid

A stirred mixture of 3-amino-4-chloro-5-sulfamylbenzoic acid (40 g),concentrated hydrochloric acid (32 ml), water (100 ml), and ice (300 g)is diazotized by dropwise addition of a solution of sodium nitrite (11.5g) in water (40 ml) during 30 minutes while stirring at 0° to 5° C.After additional stirring for 30 minutes at this temperature thereaction mixture is filtered, and the filtrate is during 30 minutesadded dropwise to a stirred alkaline solution of sodium sulfide at 0° to5° C. (The sodium sulfide solution is prepared previously from 42 gsodium sulfide (Na₂ S, 9H₂ 0), sulfur (5.5 g), and 3 N sodium hydroxide(75 ml) by mixing and heating to approximately 50°C.). After stirringfor 18 hours the reaction mixture is adjusted to pH 3 by addition ofconcentrated hydrochloric acid while cooling. The precipitated disulfideis collected by filtration, washed with water and suspended in aceticacid (50 ml). The stirred suspension is thereafter boiled while zincpowder (5.5 g) is added in portions during 2 hours. After additionalboiling for 2 hours the mixture is cooled to room temperature andfiltered. The filtrate is acidified to pH 1.5 by addition ofhydrochloric acid to precipitate the crude4-chloro-3-mercapto-5-sulfamylbenzoic acid showing a melting point of263° -- 264°C. after recrystallization from ethanol.

EXAMPLE 2 3-Butylthio-4-chloro-5-sulfamylbenzoic acid

To a stirred solution of 4-chloro-3-mercapto-5-sulfamylbenzoic acid (5.5g) in 1 N sodium hydroxide (29.5 ml), butyl iodide (2.1 ml) is added.After additional stirring for 50 hours precipitates the sodium salt of3-butylthio-4-chloro-5-sulfamylbenzoic acid which is collected andwashed with ice water. The sodium salt is suspended in water (25 ml) and1 N hydrochloric acid added slowly until a pH value of 1. Theprecipitate is collected by filtration and recrystallized from aqueousethanol to yield 3-butylthio-4-chloro-5-sulfamylbenzoic acid with amelting point of 202° - 203°C.

EXAMPLE 3 Ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate

3-Butylthio-4-chloro-5-sulfamylbenzoic acid (1.8 g) in a saturatedsolution of hydrogen chloride in ethanol (40 ml) is stirred for 18hours. The precipitate is collected by filtration and washed withethanol and petroleum ether to yield ethyl3-butylthio-4-chloro-5-sulfamylbenzoate with a melting point of 160° -162°C.

EXAMPLE 4 Ethyl 3-benzylthio-4-chloro-5-sulfamylbenzoate

By replacing 3-butylthio-4-chloro-5-sulfamylbenzoic acid with3-benzylthio-4-chloro-5-sulfamylbenzoic acid and by using the proceduredescribed in example 3, ethyl 3-benzylthio-4-chloro-5-sulfamylbenzoateis obtained with a melting point of 182° - 182.5°C.

EXAMPLE 5 3-Benzylthio-4-chloro-5-sulfamylbenzoic acid

4-Chloro-3-mercapto-5-sulfamylbenzoic acid (0.27 g) is dissolved inwater (25 ml) by addition of 1 N sodium hydroxide until pH 8. Benzylbromide (0.15) is added and the reaction mixture stirred for 18 hours.Addition of 4 N hydrochloric acid until pH 1.5 precipitates a crudematerial which is collected by filtration, washed with water, andrecrystallized from aqueous ethanol to yield3-benzylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of241° - 242.5°C.

EXAMPLE 6 Ethyl 3-benzylchio4-phenylthio-5-sulfamylbenzoate

A mixture of ethyk 3-benzylthio-4-chloro-5-sulfamylbenzoate (0.77 g),thiophenol (0.36 ml), and dry ethanol (15 ml) containing 3millimoles ofsodium thiophenolate is refulxed for 20 hours. After cooling theprecipitate is collected by filtration to yield ethyl3-benzylthio-4-phenylthio-5-sulfamylbenzoate with a melting point of151° - 152°C.

EXAMPLE 7 3-Benzylthio-4-phenylthio-5-sulfamylbenzoic acid

A mixture of ethyl 3-benzylthio-4-phenylthio-5-sulfamylbenzoate (0.35g), 1 N sodium hydroxide (10 ml), and ethanol (5 ml) is stirred for 10minutes. The resulting solution is boiled for 2 minutes and isthereafter left for 1 hour to reach room temperature. 1 N hydrochloricacid (10.5 ml) is added to precipitate3-benzylthio-4-pnenylthio-5-sulfamylbenzoic acid. After collection byfiltration and recrystallization from aqueous ethanol the compound isobtained with a melting point of 208° - 209°C.

EXAMPLE 8 3-Benzylsulfonyl-4-chloro-5-sulfamylbenzoic acid

A mixture of 3-benzylthio-4-chloro-5-sulfamylbenzoic acid (0.75 g),acetic acid (25 ml), and hydrogen peroxide (2 ml of an 30% aqueoussolution) is stirred for 2 days at room temperature. Addition of water(100 ml) precipitates 3-benzylsulconyl-4-chloro-5-sulfamylbenzoic acid.After collection by filtration and recrystallization from aqueousethanol the compound crystallizing with one mole of water, is obtainedwith a melting point of 236° - 237°C.

EXAMPLE 9 3-Butylthio-4-phenylthio-5-sulfamylbenzoic acid

A mixture of ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate (0.85 g),thiophenol (0.6 ml), and dry ethanol (25 ml) containing 5 millimoles ofsodium thiophenolate is refluxed for 6 hours. After evaporation in vacuo1 N sodium hydroxide (20 ml) and ethanol (10 ml) are added, and themixture is refluxed for 15 minutes. After cooling and extraction withdiethyl ether, 3-butylthio-4-phenylthio-5-sulfamylbenzoic acid isprecipitated from the aqueous layer by addition of 4 N hydrochloricacid. The precipitate is collected by filtration and recrystallized fromaqueous ethanol to yield the desired acid having a melting point of192° - 193°C.

EXAMPLE 10 5-Amino-3-mercapto-4-phenoxybenzoic acid A. Mono sodium saltof 4-chloro-5-nitro-3-sulfinobenzoic acid

Sodium sulfite (20 g) is added to water (60 ml) and while stirring andkeeping the temperature between 15°C and 20°C,4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid (16 g) is added inportions during 2 hours. The reaction mixture is kept at pH 8 by adding2 N sodium hydroxide via an automatical end-point titrator. After thebase consume has ceased, the mono sodium salt of4-chloro-5-nitro-3-sulfinobenzoic acid is precipitated from the solutionby addition of concentrated hydrochloric acid (40 ml) at 5°C. The acidicsalt is collected by filtration, recrystallized from water (30 ml) andobtained with a melting point of 219°C (decomposition).

B. Mono sodium salt of 5-nitro-4-phenoxy-3-sulfinobenzoic acid

A mixture of mono sodium salt of 4-chloro-5-nitro-3-sulfinobenzoic acid(13.3 g), sodium hydrogen carbonate (20 g), phenol (14 g), and water(100 ml) is heated to 85°C and kept at this temperature for 40 hours.Then the reaction mixture is extracted with diethyl ether, and theaqueous layer acidified with 4 N hydrochloric acid. The precipitatedmono sodium salt of 5-nitro-4-phenoxy-3-sulfinobenzoic acid is collectedby filtration and recrystallized from water, and dried in vacuo at115°C. The acid is obtained with a melting point of 227°C(decomposition).

C. 5-Amino-3-mercapto-4-phenoxybenzoic acid

Zinc powder (38 g) is added to warm solution (70°C) of the mono sodiumsalt of 5-nitro-4-phenoxy-3-sulfinobenzoic acid (10 g) in ethanol (190ml), and while stirring 5 N hydrochloric acid (190 ml) is addeddropwise. The reaction mixture is kept under nitrogen for an additional2 hours at 70°C. After cooling and filtration, the ethanol is distilledoff in vacuo. After standing in a refrigerator for 16 hours, theprecipitated material is collected by filtration and washed withconcentrated hydrochloric acid (15 ml). This material is then suspendedin water (300 ml) and the pH adjusted to 2 by addition of 2 N sodiumhydroxide. The obtained crude 5-amino-3-mercapto-4-phenoxybenzoic acidis collected and recrystallized from aqueous ethanol. The acid isobtained with a melting point of 199° - 200°C.

EXAMPLE 11 5-Amino-3-mercapto-4-phenylthiobenzoic acid A. Mono sodiumsalt of 5-nitro-4-phenylthio-3-sulfinobenzoic acid

A mixture of mono sodium salt of 4-chloro-3-nitro-5-sulfinobenzoic acid(18 g), sodium hydrogen carbonate (26 g), thiophenol (6 ml) and water(130 ml) is stirred at 85°C for 6 hours. After cooling, the reactionmixture is adjusted to pH 2 by addition of 2 N hydrochloric acid. Theprecipitated mono sodium salt of 3-nitro-4-phenylthio 5-sulfinobenzoicacid is collected by filtration, recrystallized from water and dried at115°C in vacuo.

B. 5-Amino-3-mercapto-4-phenythiobenzoic acid

Zinc powder (32 g) is added to warm solution (70°a of the mono sodiumsalt of 5-nitro-4-phenylthio-3-sulfinobenzoic acid (11 g) in ethanol(220 ml), and while stirring, 5 N hydrochloric acid (220 ml) is addeddropwise. The reaction mixture is stirred for additional 2 hours at70° - 80°C. After filtration the ethanol is distilled off in vacuo, andthe reaction mixture adjusted to pH 2 by addition of concentrated sodiumhydroxide. The mother liquor is decanted off and the resulting solidreaction product warmed on s steam-bath for 5 minutes after addition of1 N sodium hydroxide (300 ml). After filtration and subsequent cooling,5-amino-3-mercapto-4-phenylthiobenzoic acid is precipitated by additionof 4 N hydrochloric acid until pH 2. After collection andrecrystallization from aqueous ethanol, the compound is obtained with amelting point of 173.5° - 174.5°C.

EXAMPLE 12 5-Amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid A. Monosodium salt of 4-(p-methoxyphenoxy)-5-nitro-3-sulfinobenzoic acid.

A mixture of mono sodium salt of 4-chloro-5-nitro-3-sulfinobenzoic acid(29 g), sodium hydrogen carbonate (30 g), p-methoxyphenol (25 g), andwater (200 ml) is slowly heated to 80°C and kept at this temperature for96 hours while stirring. After cooling, the reaction mixture isextracted twice with diethyl ether, and after addition for saturatedsodium chloride solution (200 ml) the aqueous layer is adjusted to pH1.5 by addition of concentrated hydrochloric acid. The precipitated monosodium salt of 4-(p-methoxyphenoxy)-5-nitro-3-sulfinobenzoic acid iscollected, dried in air at 20°C, and obtained with 3 moles of water ofcrystallization.

B. 5-Amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid

By replacing mono sodium salt of4-(p-methoxyphenoxy)-5-nitro-3-sulfinobenzoic acid (12 g) for the momosodium salt of 5-nitro-4-phenylthio-3-sulfinobenzoic acid (11 g) inExample 11B, 5-amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid isobtained with a melting point of 182° - 184°C.

EXAMPLE 13 5-Amino-3-mercanto-4-(p-methylphenylthio) benzoic acid A.Mono sodium salt of 4-(p-methylphenylthio)-5-nitro-3-sulfinobenzoic acid

By replacing p-methylthiophenol (12.5 g) for p-methoxyphenol in Example12, step A, and following the procedure described, the mono sodium saltof 4(p-methlphenylthio)-5-nitro-3-sulfinobenzoic acid is obtained. Thecompound is recrystallized from water, air-dried at 20°C, and therebyobtained with 2 moles of water of crystallisation.

B. 5-Amino-3-mercapto-4-(p-methylphenylthio)benzoic acid

By replacing in Example 11, step B, the mono sodium salt of4-(p-methylphenylthio)-5-nitro-3-sulfinobenzoic acid for the mono sodiumsalt of 5-nitro-4-phenylthio3-sulfinobenzoic acid and following theprocedure described, 5-amino-3-mercapto-4-(p-methylphenylthio)benzoicacid is obtained with a melting poinr of 178° - 182°C.

EXAMPLE 14 5-Amino-3-benzylthio-4-phenoxybenzoic acid

5-Amino-3-mercapto-4-phenoxybenzoic acid (0.53 g) is suspended in water(20 ml) and the pH is adjusted to 8 by addition of 1 N sodium hydroxide.Benzyl bromide (0.34 g) is added to the resulting solution, and thereaction mixture is stirred for 90 minutes temperature. By addition of 1N hydrochloric acid until pH 2.5 the5-amino-3-benzylthio-4-phenoxybenzoic acid precipitates. Aftercollection by filtration, recrystallization from ethanol and drying invacuo at 80°C, the compound is obtained with a melting point of159°-161°C.

EXAMPLE 15 5-Amino-3-ethylthio-4-phenoxybenzoic acid

5-Amino-3-mercapto-4-phenoxybenzoic acid (2.6 g) is dissolved in water(100 ml) by addition of 1 N sodium hydroxide (20 ml). Ethyl iodide (3.2g) is added, and the reaction mixture stirred for 2 hours at roomtemperature. After addition of ethanol (50 ml),5-amino-3-ethylthio-4-phenoxybenzoic acid is precipitated by addition of1 N hydrochloric acid until pH 2.5. After collection by filtration,recrystallization from aqueous ethanol and drying in vacuo at 80°C thecompound is obtained with a melting point of 154°-155°C.

EXAMPLE 16 -Amino-4-phenoxy-3-N-propylthiobenzoic acid

A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.61 g), N sodiumhydroxide (20.5 ml), and n-propyl iodide (1.5 ml) is shaken in a sealedreaction flask for 30 hours. Thereafter5-amino-4-phenoxy-3-n-propylthiobenzoic acid is precipitated by additionof 1 N hydrochloric acid to the reaction mixture until pH 2.5. Aftercollection, recrystallization from aqueous ethanol and drying in vacuoat 80°C, the compound is obtained with a melting point of 136°-137.5°C.

EXAMPLE 17 5-Amino-3-n-butylthio-4-phenoxybenzoic acid

5-Amino-3-mercapto-4-phenoxybenzoic acid (5.22 g) is suspended in water(150 ml), 1 N sodium hydroxide is added until pH 8, and n-butyl iodide(7.4 g) is added to the resulting solution. The reaction mixture isstirred for 16 hours whereafter 5-amino-3-n-butylthio-4-phenxoybenzoicacid is precipitated by addition of 1 N hydrochloric acid until pH 2.5.After collection, recrystallization from aqueous ethanol, and drying invacuo at 65°C, the compound is obtained with a melting point of131°-132°C.

EXAMPLE 18 5-Amino-3-sec-butylthio-4-phenoxybenzoic acid

A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g), sodiumhydrogen carbonate (2g), saturated sodium hydrogen carbonate (100 ml),and sec-butyl iodide (2.2 g) is stirred for 6 hours at 55°C. Aftercooling, 5-amino-3-sec-butylthio-4-phenoxybenzoic acid is precipitatedby adition of hydrochloric acid until pH 2.5. After collection,recrystallization from aqueous ethanol, and drying in vacuo at 80°C, thecompound is obtained with a melting point of 157°-158°C.

EXAMPLE 19 5-Amino-3-isobutylthio-4-phenxoybenzoic acid

By replacing isobutyl iodide (4 g) for sec-butyl iodide in Example18,5-amino-3-isobutylthio-4-phenoxybenzoic acid is obtained with amelting point of 148°-15°C.

EXAMPLE 20 5-Amino-3-n-pentylthio-4-phenoxybenzoic acid

A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (5.2 g), n-pentylbromide (5 ml), and 0.5 N sodium hydroxide is stirred at roomtemperature for 5 days. 5-Amino-3-n-pentylthio-4-phenxoybenzoic acid isprecipitated by addition of 4 N hydrochloric acid (30 ml). Aftercollection by filtration, recrystallisation from cyclohexane and drying,the compound is obtained with a melting point of 98°C.

EXAMPLE 31

5-Amine-3-isoamylthio-4-phenoxybenzoic acid

By replacing isoamyl iodide (3 g) for sec-butyl iodide in Example 18 andfollowing the procedure described with the exception that the reactionmixture is kept under nitrogen, 5-amino-3-isoamylthio-4-phenoxybenzoicacid is obtained with a melting point of 132°-133°C.

EXAMPLE 22 3-Allylthio-5-amino-4-phenoxybenzoic acid

A solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g) insaturated sodium hydrogen carbonate (120 ml) is cooled to 4°C. Whilecooling and stirring, allyl bromide (1 g) is added, and the reactionmixture is kept under nitrogen. After additional stirring for 10minutes, 3-allylthio-5-amino-4-phenoxybenzoic acid is precipitated byaddition of hydrochloric acid until pH 3. After collection byfiltration, recrystallisation from aqeuous ethanol, and drying in vacuo,the compound is obtained with a melting point of 142°-143°C.

EXAMPLE 23 5-Amino-4-phenoxy-3-propargylthiobenzoic acid

A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g), propargylbromide (1.2 g) and saturated sodium hydrogen carbonate (120 ml) isstirred for 1 hour at 55°C. Despite a partial precipitation of thesodium salt of 5-amino-4-phenoxy-3-propargylthiobenzoic acid on cooling,crude 5-amino-4-phenoxy-3-propargylthiobenzoic acid is precipitated byaddition of hydrochloric acid until pH 2.5. The acid is collected byfiltration and redissolved in boiling saturated sodium hydrogencarbonate (12 ml). After cooling, the precipitated sodium salt iscollected by filtration. The salt is redissolved in hot water (40 ml),and 5-amino-4-phenoxy-3-propargylthiobenzoic acid precipitated byaddition of 1 N hydrochloric acid until pH 2.5. After collection byfiltration and recrystallisation from aqueous ethanol, the compound isobtained with a melting point of 167°-168°C.

EXAMPLE 24 5-Amino-3-benzylthio-4-(p-methoxyphenoxy)benzoic acid

5-Amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid (2 g) is dissolvedin 1 N sodium hydrogen carbonate (50 ml), and after addition of benzylbromide (0.85 ml), the reaction mixture is stirred for 17 hours. Afterextraction twice with diethyl ether (25 ml), the aqueous layer isadjusted to pH 2 by addition of 4 N hydrochloric acid. The precipitated5-amino-3-benzylthio-4-(p-methoxyphenoxy)-benzoic acid is collected andrecrystallized from aqueous ethanol. After drying in vacuo at 80°C, thecompound is obtained with a melting point of 158°-161°C.

EXAMPLE 25 5-Amino-3-benzylthio-4-phenylthiobenzoic acid

5-Amino-3-mercapto-4-phenylthiobenzoic acid (1.6 g) is dissolved in 1 Nsodium hydrogen carbonate (50 ml), and after addition of benzyl bromide(0.7 ml), the reaction mixture is stirred for 20 hours. The resultingsuspension of the sodium salt of the reaction product is adjusted to pH2 by addition of 4 N hydrochloric acid. The precipitated5-amino-3-benzylthio-4-phenyl-thiobenzoic acid is collected byfiltration and recrystallized from aqueous ethanol to yield the compoundwith a melting point of 170.5°-172°C.

EXAMPLE 26 5-Amino-3-benzylthio-4-(p-methylphenylthio)benzoic acid

By replacing 5-amino-3-mercapto-4-(p-methylphenylthio)-benzoic acid(1.67 g) for 5-amino-3-mercapto-4-phenylthiobenzoic acid in Example 25and following the procedure described,5-amino-3-benzylthio-4-(p-methylphenylthio)-benzoic acid is obtainedwith a melting point of 177°-179°C.

EXAMPLE 27 5-Amino-4-phenoxy-3-(3-thienylmethylthio)benzoic acid

To a solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.5 g) in 0.5N sodium hydroxide (100 ml), a solution of 3-bromoethylthiophene (3.5 gin benzene (20 ml)) is added. The reacton mixture is stirred for 2 hoursat room temperature. After extraction with additional benzene, theaqueous layer is acidified by addition of 4 N hydrochloric acid toprecipitate 5-amino-4-phenoxy-3-(3-thienylmethylthio)benzoic acid. Aftercollection by filtration, recrystallisation from aqueous ethanol anddrying, the compound is obtained with a melting point of 153°-155°C.

EXAMPLE 28 3-Benzylthio-4-phenoxy-5-sulfamylbenzoic acid A.3-Benzylthio-5-chlorosulfonyl-4-phenoxybenzoid acid

To a solution of 5-amino-3-benzylthio-4-phenoxybenzoic acid (1.4 g) in0.5 N lithium hydroxide (8 ml), lithium nitrite (0.21 g) is added. Thesolution is added slowly to a mixture of acetic acid (10 ml) andconcentrated hydrochloric acid (10 ml) while stirring and keeping thetemperature at 2°^(2/35)°C. The resulting diazonium mixture is pouredinto acetic acid (20 ml), saturated with sulphur dioxide and containingcopper chloride (0.2 g CuCl₂, 2 H₂ O.). The reaction mixture is allowedto reach room temperature while stirring. After cooling, theprecipitated 3-benzyl thio-5-chlorosulfonyl-4-phenoxybenzoic acid isisolated by filtration, washed with aqueous acetic acid, and dried invacuo at room temperature.

B. 3-Benzylthio-4-phenoxy-5-sulfamylbenzoic acid

3-Benzylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (0.6 g) is added toconcentrated aqueous ammonia (10 ml). After 1 hour, the reaction mixtureis heated on a steam-bath for 15 minutes, and crude3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by additionof 1 N hydrochloric acid until pH 2.5. The crude product is dissolved inaqueous sodium hydrogen carbonate by heating. After cooling, theprecipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoicacid is collected by filtration. The salt is redissolved in hot water(20 ml) and 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitatedby addition of 1 N hydrochloric acid. After cooling and collecting byfiltration, and drying in vacuo at 80°C, the compound is obtained with amelting point of 235°-236°C.

EXAMPLE 29 3-Ethylthio-4-phenoxy-5-sulfamylbenzoic acid A.5-Chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid

To a solution of 5-amino-3-ethylthio-4-phenoxybenzoic acid (1.16 g) in 1N sodium hydroxide (4 ml), sodium nitrite (0.28 g) is added. Thesolution is added slowly to a mixture of acetic acid (10 ml) andconcentrated hydrochloric acid (10 ml) while stirring and keeping thetemperature of 2°-5°C. The resulting diazonium mixture is poured intoacetic acid (20 ml), saturated with sulphur dioxide and containingcopper chloride (0.2 g CuCl₂, 2 H₂ O). The reaction mixture is allowedto reach room temperature while stirring. After cooling, theprecipitated 3-ethylthio-5-chlorosulfonyl-4-phenoxybenzoic acid iscollected by filtration, washed with aqueous acetic acid, and dried invacuo at room temperature.

B. 3-Ethylthio-4-phenoxy-5-sulfamylbenzoic acid

5-Chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid (1 g) is added toconcentrated aqueous ammonia (20 ml) at 5°-10°C. After 30 minutes thereaction mixture is heated on a steam-bath for 1 hour while most of theexcess of ammonia was allowed to distill off. After cooling, theprecipitated ammonium salt of 3-ethylthio-4-phenoxy-5-sulfamylbenzoicacid is collected by filtration. The salt is dissolved in hot water (75ml) and the solution acidified by addition of hydrochloric acid. Aftercooling, the precipitated 3-ethylthio-4-phenoxy-5-sulfamylbenzoic acidis collected by filtration and recrystallized from aqueous ethanol toyield the compound with a melting point of 225°-227°C after drying invacuo at 80°C.

EXAMPLE 30 4-Phenoxy-3-n-propylthio-5-sulfamylbenzoic acid A.5-Chlorosulfonyl-4-phenoxy-3-n-propylthiobenzoic acid

By replacing 5-amino-4-phenoxy-3-n-propylthiobenzoic acid (1.1 g) for5-amino-3-ethylthio-4-phenoxybenzoic acid in Example 29A5-chlorosulfonyl-4-phenoxy-3-n-propylthiobenzoic acid is obtained.

B. 4-Phenoxy-3-n-propylthio-5-sulfamylbenzoic acid

By replacing 5-chlorosulfonyl-4-phenoxy-3-n-propylthiobenzoic acid for5-chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid in Example 29B,4-phenoxy-3-n-propylthio-5-sulfamylbenzoic acid is obtained with amelting point of 209°-209.5°C.

EXAMPLE 31 3-n-Butylthio-4-phenoxy-5-sulfamylbenzoic acid A.3-n-Butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid

By replacing 5-amino-3-n-butylthio-4-phenoxybenzoic acid (1.27 g) for5-amino-3-ethylthio-4-phenoxybenzoic acid in Example 29 A,3-n-butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid is obtained.

B. 3-n-Butylthio-4-phenoxy-5-sulfamylbenzoic acid

By replacing 3-n-butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid for5-chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid in Example 29 B,3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid is obtained with amelting point of 222°-224°C.

EXAMPLE 32 3-sec.-Butylthio-4-phenoxy-5-sulfamylbenzoic acid A.3-sec.-Butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid

By replacing 5-amino-3-sec.-butylthio-4-phenoxybenzoic acid for5-amino-3-ethylthio-4-phenoxybenzoic acid in Example 29 A,3-sec.-butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid is obtained.

B. 3-sec.-Butylthio-4-phenoxy-5-sulfamylbenzoic acid

3-sec.-Butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (1 g) is addedto concentrated aqueous ammonia (25 ml) at 5°-10°C. The reaction mixtureis allowed to stand at room temperature for 16 hours, whereafter 3-sec.-butylthio-4-phenoxy-5-sulfamylbenzoic acid is precipitated byaddition of 1 N hydrochloric acid until pH 2.5. After collecting byfiltration, recrystallized from aqueous ethanol and drying in vacuo at80°C, the compound is obtained with a melting point of 192°-193°C.

EXAMPLE 33 3-Isobutylthio-4-phenoxy-5-sulfamylbenzoic acid A.3-Isobutylthio-5-chlorosulfonyl-4-phenoxybenzoic acid

By replacing 5-amino-3-isobutylthio-4-phenoxybenzoic acid for5-amino-3-ethylthio-4-phenoxybenzoic acid in Example 29 A,3-isobutylthio-5-chlorosulfonyl-4-phenoxybenzoic acid is obtained.

B. 3-Isobutylthio-4-phenoxy-5-sulfamylbenzoic acid

By replacing 3-isobutylthio-5-chlorosulfonyl-4 -phenoxybenzoic acid for3-sec.-butylthio-5-chlorosulfonyl-4-phenoxybenzoic acid in Example 32 B,3-isobutylthio-4-phenoxy-5-sulfamylbenzoic acid is obtained with amelting point of 193°-194°C.

EXAMPLE 34 3-n-Pentylthio-4-phenoxy-5-sulfamylbenzoic acid

To a solution of 5-amino-3-n-pentylthio-4-phenoxybenxoic acid (1.33 g)in 1 N potassium hydroxide (4 ml), potassium nitrite (0.35 g) is added.The solution is added slowly to a mixture of acetic acid (10 ml) andconcentrated hydrochloric acid (10 ml) while stirring and keeping thetemperature at 2°-5°C. The resulting diazonium mixture is poured intoacetic acid (20 ml), saturated with sulphur dioxide and containingcopper chloride (0.2 g CuCl₂, 2 H₂ O). The reaction mixture is allowedto reach room temperature while stirring. After cooling, the aqueouslayer is decanted from the oily5-chlorosulfonyl-3-n-pentylthio-4-phenoxybenzoic acid thus formed, andthe oily product is dissolved in cooled concentrated aqueous ammonia (25ml). The reaction mixture is left to stand at room temperature for 16hours, whereafter 3-n-pentylthio-4-phenoxy-5-sulfamylbenzoic acid issprecipitated by acidification with 4 N hydrochloric acid. Aftercollection by filtration, recrystallisation from aqueous ethanol anddrying, the compound is obtained with a melting point of 180°-182°C.

EXAMPLE 35 3-Isoamylthio-4-phenoxy-5-sulfamylbenzoic acid A.5-Chlorosulfonyl-3-isoamylthio-4-phenoxybenzoic acid

By replacing in Example 29A 5-amino-3-isoamyltho-4-phenoxybenzoic acid(1.33 g) for 5-amino-3-ethylthio-4-phenoxybenzoic acid and following theprocedure described, 5-chlorosulfonyl-3-isoamylthio-4-phenoxybenzoicacid is obtained with a melting point of 168°-169°C.

B. 3-Isoamylthio-4-phenoxy-5-sulfamylbenzoic acid

By replacing in Example 29B5-chlorosulfonyl-3-isoamylthio-4-phenoxybenzoic acid for5-chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid and following theprocedure described, the ammonium salt and the free acid of3-isoamylthio-4-phenoxy-5-sulfamylbenzoic acid is provided. The acid isobtained with a melting point of 226°-227°C.

EXAMPLE 36 3-Allylthio-4-phenoxy-5-sulfamylbenzoic acid A.3-Allylthio-5-chlorosulfonyl-4-phenoxybenzoic acid

By replacing in Example 29A 3-allylthio-5-amino-4-phenoxybenzoic acid(1.2 g) for 5-amino-3-ethylthio-4-phenoxybenzoic acid and following theprocedure described, 3-allylthio-5-chlorosulfonyl-4-phenoxybenzoic acidis obtained with a melting point of 160°-162°C.

B. 3-Allylthio-4-phenoxy-5-sulfamylbenzoic acid

3-Allylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (1 g) is dissolved incooled concentrated aqueous ammonia (20 ml) while stirring. After 1 hourthe reaction mixture is heated on a steam bath for 5 minutes, cooled,and 3-allylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated byaddition of 4 N hydrochloric acid. After collection by filtration,recrystallisation from aqueous ethanol, and drying, the compound isobtained with a melting point of 218°-219°C.

EXAMPLE 37 4-Phenoxy-3-propargylthio-5-sulfamylbenzoic acid A.5-Chlorosulfonyl-4-phenoxy-3-propargylthiobenzoic acid

By replacing in Example 29A 5-amino-4-phenoxy-3-propargylthiobenzoicacid (1.2 g) for 5-amino-3-ethylthio-4-phenoxybenzoic acid and followingthe procedure described,5-chlorosulfonyl-4-phenoxy-3-propargylthiobenzoic acid is obtained witha melting point of 177°-179°C.

B. 4-Phenoxy-3-propargylthio-5-sulfamylbenzoic acid

By replacing 5-chlorosulfonyl-4-phenoxy-3-propargylthiobenzoic acid for5-chlorosulfonyl-3-allythio-4-phenoxybenzoic acid in Example 36B andfollowing the procedure described with the exception that the heating ona steam bath is extended to 3 hours,4-phenoxy-3-propargylthio-5-sulfamylbenzoic acid is obtained with amelting point of 197°-198°C.

EXAMPLE 38 3-Benzylthio-4-(p-methylpenylthio)-5-sulfamylbenzoic acid A.3-Benzylthio-5-chlorosulfonyl-4-(p-methylphenylthio)-benzoic acid

By replacing in Example 29A a solution of5-amino-3-benzylthio-4-(p-methylphenylthio)benzoic acid (0.76 g) andsodium nitrite (0.15 g) in 0.2 N sodium hydroxide (10 ml) for thesolution of 5-amino-3-ethylthio-4-phenoxybenzoic acid and sodium nitritein 1 N sodium hydroxide and following the procedure described,3-benzylthio-5-chlorosulfonyl-4-(p-methylphenylthio)benzoic acid isobtained with a melting point of 188°-190°C.

B. 3-Benzylthio-4-(p-methylphenylthio)-5-sulfamylbenzoic acid

3-Benzylthio-5-chlorosulfonyl-4-(p-methylphenylthio)-benzoic acid (0.5g) is added to concentrated aqueous ammonia (10 ml) while cooling andstirring. After 2 hours at room temperature, the reaction mixture isheated on a steam bath for 5 minutes, and after addition of ethanol (8ml) the 3-benzylthio-4-(p-methylphenylthio)-5-sulfamylbenzoic acid isprecipitated by addition of 4 N hydrochloric acid until pH 1.5. Aftercooling, the compound is collected by filtration, recrystallized twicefrom aqueous ethanol and air-dried at room temperatur. The compound isobtained with a melting point of 250°-251°C. crystallizing with one molof ethanol.

EXAMPLE 39 4-Phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid A.5-Chlorosulfonyl-4-phenoxy-3-(3-thienylmethylthio)-benzoic acid

To a solution of 5-amino-4-phenoxy-3-(3-thienylmethylthio)benzoic acid(3.5 g) in 1 N potassium hydroxide (10 ml). potassium nitrite (0.85 g)is added. The solution is slowly added to a mixture of acetic acid (20ml) and concentrated hydrochloric acid (20 ml) while stirring andkeeping the temperature at 2°-5°C. The resulting diazonium mixture ispoured into acetic acid (40 ml) saturated with sulpur dioxide andcontaining copper chloride (0.5 g CuCl₂, 2 H₂ O). Gaseous sulphurdioxide is bubbled through the reaction mixture which is allowed toreach room temperature while stirring. After cooling, the precipitated5-chlorosulfonyl-4-phenoxy-3-(3-thienylmethylthio)benzoic acid iscollected by filtration, washed with aqueous acetic acid, and dried invacuo at room temperature.

B. 4-Phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid

By replacing 5-chlorosulfonyl-4-phenoxy-3-(3-thienyl-methylthio)benzoicacid for 3-allylthio-5-chlorosulfonyl-4-phenoxybenzoic acid in Example36B and following the procedure described,4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid is obtainedwith a melting point of 222°-224°C.

EXAMPLE 40 3-Benzylthio-4-(p-methoxyphenoxy)-5-sulfamylbenzoic acid A.3-Benzylthio-5-chlorosulfonyl-4-(p-methoxyphenoxy)-benzoic acid

By replacing 5-amino-3-benzylthio-4-(p-methoxyphenoxy)-benzoic acid (1.1g) for 5-amino-3-ethylthio-4-phenoxybenzoic acid in Example 29 A and byusing 3 ml of 1 N sodium hydroxide and 0.21 g of sodium nitrite, the3-benzylthio-5-chlorosulfonyl-4-(p-methoxyphenoxy)-benzoic acid isobtained.

B. 3-Benzylthio-4-(p-methoxyphenoxy)-5-sulfamylbenzoic acid

By replacing 3-benzylthio-5-chlorosulfonyl-4-)p-methoxyphenoxy)-benzoicacid for 5-chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid in Example29B, the 3-benzylthio-4-(p-methoxyphenoxy)-5-sulfamylbenzoic acid isobtained with a melting point of 215°-216°C after drying in vacuo at80°C.

EXAMPLE 41 3-Benzylthio-4-phenylthio-5-sulfamylbenzoic acid A.3-Benzylthio-5-chlorosulfonyl-4-phenylthiobenzoic acid

5-Amino-3-benzylthio-4-phenylthiobenzoic acid (1.1 g), acetic acid (10ml), and concentrated hydrochloric acid (10 ml) is stirred and cooled to5°C. At this temperature a concentrated solution of sodium nitrite (0.21g) is added slowly while stirring. The resultng diazonium mixture ispoured into acetic acid (20 ml), saturated with sulphur dioxide andcontaining copper chloride (0.2 g CuCl₂, 2 H₂ O). The reaction mixtureis allowed to reach room temperature while stirring. After 30 minutes,the precipitated 3-benzylthio-5-chlorosulfonyl-4-phenylthiobenzoic acidis collected, washed with aqueous acetic acid and dried in vacuo at roomtemperature.

B. 3-Benzylthio-4-phenylthio-5-sulfamylbenzoic acid By replacing3-benzylamino-5-chlorosulfonyl-4-phenylthiobenzoic acid for5-chlorosulfonyl-3-ethyl thio-4-phenoxybenzoic acid in Example 29 B, andby dissolving the resulting ammonium salt in hot aqueous ethanol (20 ml)instead of water, the 3-benzylthio-4-phenylthio-5-sulfamylbenzoic acidis obtained with a melting point of 208°-208.5°C. EXAMPLE 423-Mercapto-4-phenoxy-5-sulfamylbenzoic acid A.5,5'-Diamino-3,3'-dicarboxy-6,6'-diphenoxydiphenyl disulfide

A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g), 1 Nsodium hydroxide, and ethanol (25 ml) is heated to 50°C. Then a solutionof iodine (1.27 g) in ethanol is added, while stirring. The reactionmixture is acidified by addition of 4 N hydrochloric acid and the5,5-diamino-3,3'-dicarboxy-6,6'-diphenoxydiphenyl disulfide isprecipitated by addition of water (100 ml). After collecting and washingwith aqueous ethanol, the desired compound is obtained with a meltingpoint of 282°-283°C.

B. 3,3'-Dicarboxy-5,5'-dichlorosulfonyl-6,6'-diphenoxydiphenyldisulfide.

To a solution of 5,5'-diamino-3,3'-dicarboxy-6,6'-diphenoxydiphenyldisulfide (2.6 g) in 1 N sodium hydroxide (10 ml), sodium nitrite (0.7g) is added. The solution is added slowly to a mixture of acetic acid(15 ml) and concentrated hydrochloric acid (15 ml), while stirring andkeeping the temperature at 2°-5°C. The resulting diazonium mixture ispoured into acetic acid (30 ml) saturated with sulfur dioxide andcontaining copper chloride (0.3 g of CuCl₂, 2 H₂ O). The reactionmixture is allowed to reach room temperature, while stirring. Afteradditional stirring for 1 hour the precipitated3,3'-dicarboxy-5,5'-dichlorosulfonyl-6,6'-diphenoxydiphenyl disulfide iscollected by filtration, washed with aqueous acetic acid, and dried invacuo at room temperature. The desired compound is obtained with amelting point of 225°C.

C. 3,3'-Dicarboxy-6,6'-diphenoxy-5,5'-disulfamyldiphenyl disulfide.

3,3'-Dicarboxy-5,5'-dichlorosulfonyl-6,6'-diphenoxydiphenyl disulfide (1g) is added to liquid ammonia (10 ml) in portions during 15 minutes.Then the excess of ammonia is allowed to distill off, while keeping thereaction flask at room temperature. The residue is dissolved in water(10 ml) and the crude disulfide precipitated by acidification with 4 Nhydrochloric acid. After collection and recrystallisation from ethanolthe 3,3'-dicarboxy-6,6'-diphenoxy-5,5'-disulfamyldiphenyl disulfide isobtained in an analytically pure state.

D. 3-Mercapto-4-phenoxy-5-sulfamylbenzoic acid

3,3'-Dicarboxy-6,6'-diphenoxy-5,5'-disulfamyldiphenyl disulfide (1.8 g)is dissolved in saturated sodium hydrogen carbonate (25 ml) afteraddition of additional sodium hydrogen carbonate (1 g). After additionof sodium dithionite (1 g) the reaction mixture is stirred at roomtemperature for 3 hours. Acidification by means of 4 N hydrochloric acidprecipitated 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid. The compoundis collected and recrystallized from ethanol/water to yield the desiredacid with a melting point of 205°-207°C.

EXAMPLE 43 3-n-Butylthio-4-phenoxy-5-sulfamylbenzoic acid A. Sodium saltof 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid

A mixture of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (0.6 g), 1 Nsodium hydrogen carbonate (25 ml), and n-butyl iodide (0.6 g) is stirredat 50°C. for 3 hours. After cooling, the precipitated sodium salt of3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid is collected and washedwith ice water. The compound crystallizes as a trihydrate.

B. 3-n-Butylthio-4-phenoxy-5-sulfamylbenzoic acid

Sodium salt of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (0.6 g) isdissolved in hot water (25 ml) and the free acid precipitated byacidification with 1 N hydrochloric acid. After cooling, the compound iscollected by filtration and recrystallized from aqueous ethanol to yield3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid with a melting point of221°-223°C., after drying in vacuo at 80°C.

EXAMPLE 44 3-Benzylthio-4-phenoxy-5-sulfamylbenzoic acid

3-Mercapto-4-phenoxy-5-sulfamylbenzoic acid (0.6 g) is suspended inwater (20 ml) and the pH is adjusted to 8 by addition of 1 N sodiumhydroxide. Benzyl bromide (0.35 g) is added to the resulting solution,and the reaction mixture is stirred for 2 hours at room temperature.After cooling, the precipitated sodium salt of3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected byfiltration. The salt is dissolved in hot water (60 ml) and the solutionacidified by addition of 1 N hydrochloric acid. After cooling, theprecipitated 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collectedby filtration and recrystallized from aqueous ethanol to yield thedesired compound with a melting point of 234°-236°C., after drying invacuo.

EXAMPLE 45 3-(2-Furylmethylthio)-4-phenoxy-5-sulfamylbenzoic acid

To a solution of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.6 g) indiethylene glycol diethyl ether (15 ml), anhydrous potassium carbonate(0.5 g) and trimethylfurfurylammonium iodide (2 g) were added. Theresulting mixture is stirred at 110°C. for 4 hours, cooled and pouredinto 0.3 N sodium hydroxide (75 ml). After extraction twice with diethylether, the aqueous layer is adjusted to pH 3 by addition of acetic acid.The reaction product is extracted with ethyl acetate, and the resultingorganic solution is evaporated in vacuo. The residue is triturated withaqueous acetone giving rise to crystallisation. The3-(2-furylmethylthio)-4-phenoxy-5-sulfamylbenzoic acid thus obtained isrecrystallized from aqueous ethanol and dried. The compound is obtainedwith a melting point of 214°-216°C.

EXAMPLE 46 4-Phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid

A mixture of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.7 g), sodiumhydrogen carbonate (1 g), sodium dithionite (1 g), 4-vinylpyridine (0.8ml) and saturated aqueous sodium hydrogen carbonate (17 ml) is stirredat 70°C. for 4 hours. After cooling, pH of the mixture is adjusted to4.5 by addition of acetic acid. The precipitated material is collectedby filtration, washed with water, and recrystallized from aqueousethanol to yield 4-phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoicacid.

EXAMPLE 47 Methyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate

A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.5 g) andmethanol (75 ml) is saturated with gaseous hydrogen chloride. Thereaction mixture is allowed to warm during saturation. After cooling andstanding for 5 hours, the reaction mixture is evaporated in vacuo. Theresidue is triturated with water and sufficient sodium hydrogencarbonate to neutralize traces of hydrochloric acid. The precipitatedmethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate is collected andrecrystallized from methanol/water to yield the ester with a meltingpoint of 122°-123°C.

EXAMPLE 48 Methyl 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoate

By replacing in Example 474-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid for3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid and following theprocedure described, methyl4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoate is obtained with amelting point of 148°-149°C.

EXAMPLE 49 Cyanomethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate

A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.3 g),chloroacetonitrile (1.4 g), triethylamine (0.61 g), and dry acetone (20ml) is refluxed for 20 hours. After cooling the triethylaminehydrochloride formed is removed by filtration, and the filtrate isevaporated in vacuo. To the residue, water (35 ml) and ethylacetate (75ml) are added, and the pH of the aqueous layer is adjusted to pH 7.5 byaddition of 4 N hydrochloric acid. The organic layer is then separated,washed with diluted sodium hydrogen carbonate, dried and evaporated invacuo. The residue is crystallized from chloroform petroleum ether toyield cyanomethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate with amelting point of 134°-135°C.

What we claim is:
 1. A compound of the formula I ##SPC7##in which R₁ isselected from the group consisting of methyl and ethyl radicalsmonosubstituted with furyl, thienyl, and pyridyl; R₂ stands for a phenylradical, optionally being substituted with a member selected from thegroup consisting of lower alkyl, hydroxy and lower alkoxy; X stands fora member selected from the group consisting of oxygen and sulphur; andpharmaceutically acceptable, non-toxic salts of the carboxylic acid offormula I; and esters thereof with cyanomethanol, benzyl alcohol, and C₁-C₆ alkanols.
 2. A compound as claimed in claim 1, in which R₂ standsfor phenyl; and R₁, and X have the meaning defined in claim
 1. 3. Acompound as claimed in claim 1, in which R₂ stands for (loweralkyl)phenyl; and R₁, and X have the meaning defined in claim
 1. 4. Acompound as claimed in claim 1, in which R₂ stands for hydroxyphenyl;and R₁, and X have the meaning defined in claim
 1. 5. A compound asclaimed in claim 1, in which R₂ stands for (lower alkoxy)phenyl; and R₁,and X have the meaning defined in claim
 1. 6. A compound as claimed inclaim 1, in which X stands for oxygen; and R₁, and R₂ have the meaningsdefined in claim
 1. 7. A compound as claimed in claim 1, in which Xstands for sulphur; and R₁, and R₂ have the meanings defined in claim 1.8. 3-(2-Furylmethylthio)-4-phenoxy-5-sulfamylbenzoic acid; andpharmaceutically acceptable, non-toxic salts thereof; and esters thereofwith cyanomethanol, benzyl alcohol, and C₁ -C₆ alkanols. 9.4-Phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid; andpharmaceutically acceptable, non-toxic salts thereof; and esters thereofwith cyanomethanol, benzyl alcohol, and C₁ -C₆ alkanols. 10.4-Phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid; andpharmaceutically acceptable, non-toxic salts thereof; and esters thereofwith cyanomethanol, benzyl alcohol, and C₁ -C₆ alkanols.